Acute lung injury (ALI) is a condition of acute respiratory failure resulting from acute pulmonary inflammation. The airway epithelium provides a complex physical and biochemical barrier to inhaled particles, allergens, and environmental toxins and thus plays a vital role in host defense. Disruption of epithelial integrity is a major contributor to increased permeability and alveolar flooding with protein-rich edema fluid, a hallmark of ALI. However, understanding of the responses of the pulmonary epithelium to injury remains incomplete. E-cadherin-modulated adhesion junction plays a critical role since the formation of adhesion junction subsequently leads to the formation of other cell junctions. Lipopolysaccharide (LPS)-induced lung injury is a very useful experimental model for the investigation and characterization of immunopathogenic changes and mechanisms in ALI. We and others have found that cytoplasmic mislocalization of E-cadherin in pulmonary epithelium induces epithelial shedding and increases pulmonary epithelial permeability in a LPS-induced murine model of ALI and in primary cultured pulmonary epithelial cells. Also, several studies from ours and others have indicated an association between E-cadherin and tyrosine kinase receptor, such as c-Met tyrosine kinase, suggesting a complex molecular mechanisms of regulation of E-cadherin localization in epithelial cells. We recently reported that lysophosphatidic acid (LPA), a bioactive phospholipid growth factor released from activated platelets, enhances innate immunity and attenuates adaptive immunity via increasing IL-8, PGE2, and IL-13R alpha2 secretion in human bronchial epithelial cells (HBEpCs). However, molecular mechanisms of pulmonary epithelial barrier function are poorly defined and in this proposal it is hypothesized that LPA post-treatment protects against pulmonary epithelial barrier dysfunction caused by LPS through cross-talk between LPA-Rs and c-Met resulting in enhanced E-cadherin accumulation at cell-cell junctions. The following Specific Aims will address the role and regulation of LPA-mediated barrier function in respiratory epithelium using primary human bronchial epithelial cells, alveolar type II epithelial cells, alveolar type II cell line and a murine model of ALI. Specific aim #1 will define the protective role of LPA in LPS-induced epithelial barrier dysfunction via restoring E-cadherin accumulation at cell-cell junctions. Specific aim #2 will characterize role of the cross-talk between G-protein-coupled LPA receptors and c-Met receptor tyrosine kinase in LPA-mediated c-Met and E-cadherin redistribution to cell-cell junctions and LPA attenuation of LPS mediated pulmonary epithelial barrier dysfunction. Specific aim #3 will characterize the role of LPA posttreatment in protecting against LPS-induced lung injury in mice. These studies will identify the molecular mechanisms linking the LPA signaling pathways involving LPA receptors to the pulmonary epithelium barrier function, which is critical to the development of new therapies directed at ameliorating lung inflammatory diseases.